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De Novo and Inherited Variants in DDX39B Cause a Novel Neurodevelopmental Syndrome

Booth et al., Brain. 2025.

https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaf035/8004980?login=true

DDX39B is a core component of the TRanscription-EXport (TREX) super protein complex. Recent studies have highlighted the important role of TREX subunits in neurodevelopmental disorders. Researchers describe a cohort of six individuals (male and female) from five families with disease-causing de novo missense variants or inherited splice-altering variants in DDX39B. Three individuals in the cohort are affected by mild to severe developmental delay, hypotonia, history of epilepsy or seizure, short stature, skeletal abnormalities, variable dysmorphic features, and microcephaly. Using a combination of patient genomic and transcriptomic data, in silico modeling, in vitro assays, and in vivo Drosophila and zebrafish models, this study implicates disruption of DDX39B in a novel neurodevelopmental disorder called TREX-complex-related neurodevelopmental syndrome. Supported by ORIP (U54OD030165).

Dysregulation of mTOR Signalling Is a Converging Mechanism in Lissencephaly

Zhang et al., Nature. 2025.

https://pubmed.ncbi.nlm.nih.gov/39743596

Lissencephaly (smooth brain) is a rare genetic condition, with such symptoms as epilepsy and intellectual disability and a median life expectancy of 10 years. This study reveals that reduced activity of the mTOR pathway may be a common cause of lissencephaly. Researchers used laboratory-grown brain models (organoids) and sequencing and spectrometry techniques to identify decreased mTOR activation in two types of lissencephaly disorders: p53-induced death domain protein 1 and Miller–Dieker lissencephaly syndrome. Pharmacological activation of mTOR signaling with a brain-selective mTORC1 activator molecule, NV-5138, prevented and reversed the morphological and functional defects in organoids. These findings suggest that mTOR dysregulation contributes to the development of lissencephaly spectrum disorders and highlight a potential druggable pathway for therapy. Supported by ORIP (S10OD018034, S10OD019967, S10OD030363), NCATS, NHGRI, NICHD, NIDA, NIGMS, NIMH, and NINDS.

Plural Molecular and Cellular Mechanisms of Pore Domain KCNQ2 Encephalopathy

Abreo et al., eLife. 2025.

https://pmc.ncbi.nlm.nih.gov/articles/PMC11703504

This study investigates the cellular and molecular mechanisms underlying KCNQ2 encephalopathy, a severe type of early-onset epilepsy caused by mutations in the KCNQ2 gene. Researchers describe a case study of a child with a specific KCNQ2 gene mutation, G256W, and found that it disrupts normal brain activity, leading to seizures and developmental impairments. Male and female Kcnq2G256W/+ mice have reduced KCNQ2 protein levels, epilepsy, brain hyperactivity, and premature deaths. As seen in the patient study, ezogabine treatment rescued seizures in mice, suggesting a potential treatment avenue. These findings provide important insights into KCNQ2-related epilepsy and highlight possible therapeutic strategies. Supported by ORIP (U54OD020351, S10OD026804, U54OD030187), NCI, NHLBI, NICHD, NIGMS, NIMH, and NINDS.

Commentary: The International Mouse Phenotyping Consortium: High-Throughput In Vivo Functional Annotation of the Mammalian Genome

Lloyd, Mammalian Genome. 2024.

https://pubmed.ncbi.nlm.nih.gov/39254744

The International Mouse Phenotyping Consortium (IMPC), a collectively governed consortium of 21 academic research institutions across 15 countries on 5 continents, represents a groundbreaking approach in genetics and biomedical research. Its goal is to create a comprehensive catalog of mammalian gene function that is freely available and equally accessible to the global research community. So far, the IMPC has uncovered the function of thousands of genes about which little was previously known. By 2027, when the current round of funding expires, the IMPC will have produced and phenotyped nearly 12,000 knockout mouse lines representing approximately 60% of the human orthologous genome in mice. This new knowledge has produced numerous insights about the role of genes in health and disease, including informing the genetic basis of rare diseases and positing gene product influences on common diseases. However, as IMPC nears the end of the current funding cycle, its path forward remains unclear. Supported by ORIP (UM1OD023221).